Cysteine proteases represent a class of peptidases characterized by the presence of a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated with the normal degradation and processing of proteins. However, abnormal activity of cysteine proteases, e.g., as a result of increased expression or enhanced activation, has been shown to have pathological consequences. Examples of cysteine proteases are cathepsins B, K, L, and S.
In particular, the normal protease activity of cathepsin S or its increased expression and activity are associated with a wide range of disease states. In particular, cathepsin S is implicated in Alzheimer's disease, and in certain autoimmune disorders, including, but not limited to juvenile onset diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, pemphigus vulgaris, Graves' disease, myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis, neuropathic pain, and Hashimoto's thyroiditis. In addition, cathepsin S is implicated in: allergic disorders, including, but not limited to, asthma; and allogenic immune responses, including, but not limited to, rejection of organ transplants or tissue grafts, or immune response to therapeutic agents. Altered expression or activity of cathepsin S has also been implicated in atherosclerosis and the rupture of atherosclerotic plaque.
In view of the number of diseases or conditions related to the activity or the increased expression of cathepsin S, compounds that are capable of inhibiting such activity or expression would accordingly be useful as therapeutic agents for the treatment of certain autoimmune disorders, neuropathic pain, Alzheimer's disease, and atherosclerosis.
In U.S. Patent Application 2008/0214676, and U.S. patent application Ser. No. 12/060,774, the complete disclosures of which is hereby incorporated by reference, a series of compounds useful as cathepsin S inhibitors were disclosed. One of those compounds, (S)—N-(1-cyanocyclopropyl)-5-cyclopropyl-4,4-difluoro-2-((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino)pentanamide, has been chosen for further study as a clinical candidate for the treatment of conditions related to the activity or the increased expression of cathepsin S. Accordingly, an efficient method of preparing this compound on a large scale is desired, particularly a method of preparing the final intermediate, (S)-methyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate or (5)-ethyl 2-amino-5-cyclopropyl-4,4-difluoropentanoate.